The insulin receptor possesses tyrosine-specific protein kinase activity. Multiple lines of evidence strongly support the hypothesis that this tyrosine kinase plays an important role in coupling insulin binding to insulin action. Nevertheless, the precise role of the tyrosine kinase activity has not been elucidated in detail. To address this question, we have attempted to identify physiologically important substrates for phosphorylation by the insulin receptor. We have identified one such substrate (pp120) which is a 120 kilodalton glycoprotein localized to the plasma membrane fraction of hepatocytes. In addition to serving as a substrate for the insulin receptor, pp120 can be phosphorylated by the hepatic epidermal growth factor receptor. Most importantly, it has been recently shown that insulin stimulates phosphorylation of tyrosine residues of pp120 in intact hepatoma cells.